Field of the Invention
The invention relates to a method of reducing inflammation in animals. More particularly, the invention relates to the combination of egg product and glucosamine to produce a synergistic effect in reducing inflammation, and particularly arthritis, in animals.
Inflammation, as defined in Dorland""s Medical Dictionary, is xe2x80x9ca localized protective response, elicited by injury or destruction of tissues, which serves to destroy, dilute or wall off both the injurious agent and the injured tissue.xe2x80x9d It is characterized by fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces, and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema, edema, hyperalgesia (tenderness), and pain.
During this complex response, chemical mediators such as histamine, 5-hydroxytryptamine, various chemotactic compositions, bradykinin, leukotrienes, and prostaglandins are liberated locally. Phagocytic cells migrate into the area, and cellular lysosomal membranes may be ruptured, releasing lytic enzymes. All of these events can contribute to the inflammatory response.
In the particular case of rheumatoid arthritis, the resulting inflammation likely involves the combination of an antigen with an antibody complement causing the local release of chemotactic and chemoactivating compositions that attract leukocytes. The leukocytes phagocytose the complexes of antigen-antibody and complement, and also release the many enzymes contained in their lysosomes. These lysosomal enzymes then cause injury to cartilage and other tissues, and this furthers the degree of inflammation. Cell-mediated immune reactions may also be involved. Prostaglandins, which are key intracellular regulators of cellular function, are also released during this process.
The inflammatory response is any response characterized by inflammation as defined above. It is well known, to those skilled in the medical arts, that the inflammatory response causes much of the physical discomfort (i.e., pain and loss of function) that has come to be associated with different diseases and injuries.
Arthritis manifests itself in a variety of forms. Some of the more common forms include rheumatoid arthritis, osteoarthritis and generalized rheumatism.
Rheumatoid arthritis is an autoimmune disease characterized by pain, swelling and stiffness in the joints. Rheumatoid arthritis is a disease which afflicts approximately 3% of Americans, and particularly women. Rheumatoid arthritis is an extremely disabling disease and usually strikes adults between the ages of 30 and 40 years, while the occurrence of clinical illness is greatest among those aged 40-60 years. Although drug therapy is somewhat effective, as many as 7% of rheumatoid arthritis sufferers are disabled to some extent as quickly as 5 years after disease onset, and within 10 years, as many as 50% are too disabled to work.
Osteoarthritis produces similar symptoms to rheumatoid arthritis. In particular, although osteoarthritis begins as a degeneration of particular cartilage whereas rheumatoid arthritis begins as inflammation in the synovium, each process approaches the other as the disease progresses. In osteoarthritis, as cartilage deteriorates and joint congruence is altered, a reactive synovitis often develops.
Conversely, as rheumatoid arthritis erodes cartilage, secondary osteoarthritis changes in bone and cartilage develop. At the end stages of both osteoarthritis and rheumatoid arthritis, the involved joints appear the same.
Some other forms of arthritis include Ankylosing Seronegative Spondyloarthropathy (ankylosing spondylitis) and reactive arthritis. These conditions are often referred to as the xe2x80x9cB-27 associated diseases,xe2x80x9d and are difficult to differentiate from rheumatoid arthritis. In some cases ankylosing spondylitis, Reiters syndrome or psoriatic arthritis are present coincidingly with Rheumatoid Arthritis in the same patient. In many cases, these patients are treated with the same disease modifying drugs as those suffering from progressive rheumatoid arthritis.
Onset of arthritis generally occurs after the age of 30 in those who are susceptible to such disease. However, some forms of arthritis may be initiated by different causes, such as slow virus infections. Because there is great overlap, many physicians consider these forms as xe2x80x9cgeneralized rheumatismxe2x80x9d and approach management of the diseases in the same way. Some diseases which fall into this category include Chronic Fatigue Syndrome, fibromyalgia (fibrositis) and gout. In fact, for some patients, evidence is accumulating for superimposition of rheumatoid arthritis and fibromyalgia.
As stated above, rheumatoid arthritis is an autoimmune disease, and as such, its etiology is much the same as the etiology of any other autoimmune disease. The body normally recognizes the difference between its own by-products and foreign invaders (i.e. bacteria, viruses, fungi and protozoans, to name a few). When an immune cell (T or B lymphocyte) reacts to a xe2x80x9cself-proteinxe2x80x9d during its development, that cell is deemed defective and usually destroyed or inactivated. Sometimes, however, a xe2x80x9cself-reactivexe2x80x9d immune cell will escape destruction. At a certain later time, that cell can be activated and trigger an immune response. Activation is thought to occur after infection with a common bacteria or virus which contains a polypeptide having a stretch of amino acids which match a stretch on the defective self-protein. Several bacteria, such as Streptococcus, Mycoplasma, and borrelia, have been implicated in the initiation of the disease, as well as certain viruses, namely retroviruses. In addition to Rheumatoid Arthritis, autoimmunity often results in such diseases as juvenile diabetes, multiple sclerosis, Graves"" disease, Meneri""s disease, myasthenia gravis, lupus erythematosus and psoriasis. (Medical Sciences Bulletin, September, 1994).
Autoimmunity affects specific organs. For example, some autoimmune diseases of liver bile ducts, and kidneys are: primary biliary cirrhosis, necrotizing glomerulonephritis, xe2x80x9cidiopathicxe2x80x9d crescentic glomerulonephritis, virus-induced liver and kidney disease, chronic hepatitis, autoimmune and drug-induced hepatitis (Gershwin, Manns, and Mackay 1992). Immune destruction of the islets of Langerhans results in diabetes mellitus (Hagopian and Lerumark 1992) and insulin autoantibodies have been described (Palmer 1987).
There are a large category of systemic vasculitides diseases in which autoimmune mechanisms have been suggested as the cause of the pathogenesis. Some of the diseases are: leukocytoclastic angitis, polyarteritis nodosa, Goodpasture""s syndrome, Kawasaki disease, Wegener""s granulomatosis, Churg-Struass syndrome, giant-cell arteritis, Takayasu arteritis, immune-complxc3xax-mediated, lupus, rheumatoid, and cryoglobulinemic vasculitis, Henoch Schonlein purpura (Kallenberg, 1996; Jennette, Jones, Falk, 1992).
There is also a body of evidence that autoimmunity may play a role in many forms of heart disease including: postpericardiotomy and post myocardial infarction syndromes, myocarditis, and idiopathic dilated cardiomyopathy. Autoimmunity may be responsible for the progression of acute disease of heart muscle to degenerative (Rose, Neumann, Burek, Herskowitz 1992).
Symptomatic involvement of skeletal muscle is common in many autoimmune diseases such as polymyositis or inflammatory myopathy (which may include rheumatoid arthritis, polymyalgia rheumatica, myasthenia gravis, myasthenic myopathy, neurogenic atrophy, motor neuron disease, fibromyalgia, fibrositis, muscular dystrophy, endocrine, metabolic, and carcinomatous myopathy). (Hollingsworth, Dawkins, Thomas 1992).
Other diseases with autoimmune origins may be uveitis, Vogt-Koyanagi-Harada syndrome, (Detrick and Hooks 1992), and Sjxc3x6gren""s syndrome, scieroderma, ankylosing spondylitis, dermatomyositis, psoriasis, psoriatic arthritis, Reiter""s syndrome (NIH 1994).
Also evidence of autoantibodies has been found in Alzheimer""s disease (Singh et al., 1992), dementia complex (Mastroianni et al., 1991) and autistic children (Singhi et al., 1993).
Several neurologic diseases such as Sydenhar""s Chorea, chronic obsessive-compulsive disorders (OCD), attention deficit hyperactivity disorder (ADHD), Tourette""s Syndrome (TS) and some cases of schizophrenia may have an auto-immune component and may be associated with anti-neuronal antibodies (Medical Sciences Bulletin, September 1994).
This summary is not all inclusive and those in the art are familiar with other autoimmune diseases, such as, for example Guillain-Barrxc3xa9syndrome (idiopathic polyneuritis).
In order to treat inflammatory related disorders, it is a common medical practice to administer pharmacologic a l agents that reduce the physical discomfort of the inflammatory response. Agents having these properties are classified as anti-inflammatory. Anti-inflammatory drugs are used for the treatment of a wide spectrum of disorders , and the same drugs are often used to treat different diseases. Treatment with anti-inflammatory drugs is not for the disease, but most often for the symptom (i.e., inflammation).
The anti-inflammatory , analgesic, and anti-pyretic drugs are a heterogeneous group of compounds, often chemically unrelated, which nevertheless share certain therapeutic actions and side effects. Corticosteroids represent the most widely-used class of compounds for the treatment of inflammation. Proteolytic enzymes represent another class of compounds that are thought to have anti-inflammatory effects. Hormones that directly or indirectly cause the adrenal cortex to produce and secrete steroids represent another class of anti-inflammatory compounds. Unfortunately, the natural and synthetic corticosteroid preparations cause a number of severe side effects, including elevation of blood pressure, salt and water retention, kidney damage and increased potassium and calcium excretion. Moreover, corticosteroids may mask the signs of infection and enhance dissemination of infectious microorganisms. These hormones are considered unsafe for use in pregnant women, and long-term corticosteroid treatment has been associated with gastric hyperactivity and/or peptic ulcers. Treatment with corticosteroids may also aggravate diabetes mellitus, requiring higher doses of insulin, and may produce psychotic disorders. Hormonal anti-inflammatory agents which indirectly increase the production of endogenous corticosteroids have the same potential for adverse side-effects.
Another common treatment for inflammation, and in particular rheumatoid arthritis, other arthritis and other autoimmune diseases, is drug therapy. In general, patients are initially treated with xe2x80x9cfirst-linexe2x80x9d agents, usually non-steroidal anti-inflammatory drugs (NSAIDs) which primarily relieve the symptoms. The patients are later treated with xe2x80x9csecond-linexe2x80x9d or disease-modifying agents (DMARDs) such as methotrexate, gold compounds, penicillamine, sulfasalazine, and antimalarial drugs. However, all of the above drugs have serious side effects, especially when administered in elevated doses. For example aspirin, an NSAID, may produce indigestion and stomach pain; phenylbutazone may produce stomach ulcers and phenacetin may lead to kidney disease. Methotrexate may cause oral ulceration and gastrointestinal (GI) side effects.
If a natural food product having anti-inflammatory effects could be obtained, it would provide an easily administratable, readily available, and safe therapeutic composition for the treatment of arthritis, autoimmune diseases and inflammation in general.
Various genera of the class Aves, such as chickens (Gallus domesticus), turkeys, and ducks, produce antibodies in blood and eggs against immunogens that cause avian diseases, as well as against other immunogens. For example, LeBacq-Verheyden et al. (Immunology 27:683 (1974)) and Leslie, G. A., et al. (J. Med. 130:1337 (1969)), have quantitatively analyzed immunoglobulins of the chicken. Polson, A., et al. (Immunological Communications 9:495-514 (1980)) immunized hens against several proteins and natural mixtures of proteins, and detected IgY antibodies in the yolks of the eggs. Fertel, R., et al. (Biochemical and Biophysical Research Communications 102:1028-1033 (1981)) immunized hens against prostaglandins and detected antibodies in the egg yolk. Jensenius et al. (Journal of Immunological Methods 46:63-68 (1981)) provide a method of isolating egg yolk IgG for use in immunodiagnostics. Polson et al. (Immunological Communications 9:475-493 (1980)) describe antibodies isolated from the yolk of hens that were immunized with a variety of plant viruses.
U.S. Pat. No. 4,357,272 discloses the isolation of antibodies from the yolks of eggs derived from hyperimmunized hens. The hyperimmunization was elicited by repetitive injections of immunogens derived from plant viruses, human IgG, tetanus antitoxin, snake antivenins, and Serameba. U.S. Pat. No. 4,550,019 discloses the isolation from egg yolks of antibodies raised in the hen by hyperimmunization with immunogens having a molecular or particle weight of at least 30,000. The immunogens used to hyperimmunize the chickens were selected from among plant viruses, human immunoglobulins, tetanus toxin, and snake venoms.
U.S. Pat. No. 4,748,018 discloses a method of passive immunization of a mammal that comprises parenterally administering purified antibody obtained from the eggs of an avian that has been immunized against the corresponding antigen, and wherein the mammal has acquired immunity to the eggs.
U.S. Pat. No. 5,772,999, assigned to DCV-Biologics, discloses a method of preventing, countering or reducing chronic gastrointestinal disorders or Non-Steroidal Anti-Inflammatory Drug-induced (NSAID-induced) gastrointestinal damage in a subject by administering hyperimmunized egg and/or milk or fractions thereof to the subject.
U.S. patent application Ser. No. 09/233,379 discloses the existence of an anti-inflammatory factor found in the egg of a hyperimmunized avian.
An immunized egg is an egg which comes from an avian which has been immunized with, for example, a specific antigen or mixture of antigens. A hyperimmunized egg is an egg which comes from an avian which has been brought to a specific state of immunization by means of, for example, periodic booster administrations of antigens. Hyperimmunized eggs, no matter the type of antigen their avian maker has been administered, have been found to have various beneficial factors, including, as mentioned above, the treatment of chronic gastrointestinal disorders, NSAID-induces gastrointestinal damage (see U.S. application Ser. No. 08/688,576) and anti-inflammatory effects due to the presence of an anti-inflammatory composition (see U.S. application Ser. No. 09/233,379).
Glucosamine a chondroprotective agent which has been studies for its potential beneficial effects in osteoarthritis. Chondroprotective agents are those which, in addition to relieving symptoms, appear to aid in balancing synthesis and degradation of cartilage tissue. Glucosamine has been known to biologists for several decades as an endogenous aminomonosaccharide synthesized from glucose. Its importance in joint dysfunctions relates to its physiologic role in the synthesis of proteoglycans and glycosaminoglycans, which are cartilage components. Research over the past four decades suggests that glucosamine is effective in reducing the symptoms of joint dysfunction and is well-tolerated. Glucosamine significantly reduces pain and tenderness and improves mobility.
Researchers have proposed several mechanisms for glucosamine""s putative benefits in joint health. In vitro studies have suggested that glucosamine affects cartilage metabolism. One such effect may be the stimulation of proteoglycan synthesis, as seen with SAMe. Another possibility is that glucosamine enhances gene expression of the chondrocyte. In addition, glucosamine may act as an anti-inflammatory agent, though the effect is 50 to 300 times lower than NSAIDs. However, the NSAID exert their anti-inflammatory effects via inhibition of the cyclooxygenase enzyme system and thereby interfering with prostaglandins, while glucosamine does not. The anti-inflammatory effect may be the result of stimulating proteoglycan synthesis, which would stabilize cell membranes. A recent in vitro study demonstrated that glucosamine increased chondrocyte adhesion to fibronectin, effectively reversing the abnormal reduction in adhesion which occurs in joint degeneration.
The invention is based on the inventors"" discovery that there is anti-inflammatory activity when egg and egg products, and in partuicular, hyperimmune egg or egg products, are combined with glucosamine and administered to a subject animal in that such administration results in the reduction, and sometime even prevention of inflammation and inflammatory related disorders in that subject animal.
In particular, the invention is directed to a composition comprising glucosamine and an egg product.
The invention is also directed to a method for reducing inflammation in a subject, the method comprising administering to the subject an effective amount of glucosamine and an egg product.
The invention is further directed to a method for reducing serum fibrinogen levels the method comprising administering to the subject an effective amount of glucosamine and an egg product.
The invention further encompasses a method for reducing or preventing the onset of rheumatoid arthritis the method comprising administering to the subject an effective amount of glucosamine and an egg product.
The invention finally covers a method for reducing or preventing the onset of osteoarthritis the method comprising administering to the subject an effective amount of glucosamine and an egg product.